Glycine encephalopathy is an inherited condition characterized by abnormally high levels of an amino acid called glycine. Glycine acts as a chemical messenger that transmits signals in the brain. Glycine encephalopathy is caused by the shortage of an enzyme that normally breaks down glycine in the body, thus allowing excess glycine to build up in tissues and organs, particularly the brain. Symptoms typically appear during infancy or early childhood and include a lack of energy (lethargy), feeding difficulties, weak muscle tone (hypotonia), abnormal jerking movements, breathing problems, seizures, and intellectual disability. It is caused by mutations in the AMT, GLDC or GCSH genes and is inherited in an autosomal recessive manner.[1][2]

Most individuals with glycine encephalopathy begin to show signs and symptoms in the first hours or first days of life (the neonatal period). Of these affected individuals, approximately 85% have a neonatal severe form, and 15% have a neonatal mild form. The signs and symptoms often include progressive lack of energy (lethargy), feeding difficulties, poor muscle tone (hypotonia), abnormal jerking movements (myoclonic jerking) and life-threatening breathing problems such as apnea.[3][1] Infants that survive this period typically have severe intellectual disability and seizures that are difficult to control.[3] Affected males are more likely to survive and tend to have more mild developmental problems than affected females, although the reason for this is unclear.[1] In rare instances, the main features of the condition improve with time; in these cases, the condition is known as transient glycine encephalopathy because glycine decreases to normal or near-normal levels after being very high at birth. Many children with the transient form will develop normally and experience few long-term medical problems, but some individuals may continue to have intellectual disability or seizures even after glycine levels decrease.[1]

There have been affected individuals with "atypical" forms of the condition with variable signs and symptoms; these forms have ranged from milder disease with onset from late infancy to adulthood, to rapidly progressing and severe disease with late onset.[1][3] The most common "atypical" form is known as the infantile form and is characterized by hypotonia, developmental delay and seizures. Individuals with this form may develop normally until signs and symptoms begin at approximately 6 months of age. As they age, many of these individuals develop intellectual disability, abnormal movements and behavioral problems. Other atypical forms of glycine encephalopathy can appear later in childhood or adulthood and cause a variety of medical problems that primarily affect the nervous system.[1]

Last updated: 10/31/2011

The Human Phenotype Ontology (HPO) provides the following list of features that have been reported in people with this condition.
Much of the information in the HPO comes from Orphanet, a European rare disease database. If available, the list includes a rough estimate of how common a feature is (its frequency).
Frequencies are based on a specific study and may not be representative of all studies. You can use the MedlinePlus Medical Dictionary for definitions of the terms below.

Glycine encephalopathy is inherited in an autosomal recessive pattern, which means in an affected individual, both copies of the gene that cause this condition have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene and are referred to as carriers. Carriers typically do not show signs and symptoms of the condition.[4] When two carriers of an autosomal recessive condition have children, each child has a 25% (1 in 4) risk to have the condition, a 50% (1 in 2) risk to be a carrier like each of the parents, and a 25% chance to not have the condition and not be a carrier.

Currently there is not a cure for glycine encephalopathy.[2][5] All but very mildly or atypically affected individuals develop intellectual disability and seizures, even with treatment. Treatment options for people with glycine encephalopathy may vary depending on the severity of their condition. Tests, such as MRI and EEG, as well as evaluations of development and neurological function can help determine the severity of the condition in an infant, child, or adult.[2]

The goal of treatment is to reduce the amount of glycine in the plasma (blood). Treatment may involve a medication called sodium benzoate, which binds with glycine allowing it to be passed out in the urine, and dextromethorphan, ketamine, or felbamate, which block some of the harmful effects of excessive glycine. These treatments may help control seizures, increase alertness, and in mildly affected individuals, improve behavior.[2] Drug dosage must be individually tailored and requires regular and careful monitoring.[2][5] Studies regarding the effectiveness of these treatments are ongoing.[2] Mildly affected individuals may receive the greatest benefit from treatment, particularly if treatment is started early.[2]

Other treatments include drugs to control seizures (anti-epileptic drugs); assistive devices or surgeries to aid with feeding and swallowing (e.g., gastrostomy tube); physical therapy; and scoliosis management. Parents and family members may benefit from genetic counseling. Click here to learn more about genetic consultations.[2]

For further details on treatment, please visit the following link to GeneReviews. GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions. Because of the complexity of the information in the article, we recommend that you review it with a health care provider.http://www.ncbi.nlm.nih.gov/books/NBK1357/#nkh.Management

The prognosis and chance of survivial for an individual affected with glycine encephalopathy depend on the form of the condition the individual has as well as complications that may arise. Preliminary data suggest that the specific mutations that an individual has can somewhat be used to predict the outcome of the disease. Mutations associated with residual enzyme activity (some functioning enzyme present) seem to be associated with a mild outcome, and two known mutations with no residual enzyme activity (no working enzyme present) seem to be associated with a severe outcome. However, because many mutations are "private" (only present in a single family) and some affected individuals die before their outcome is known, it is difficult to predict the outcome for many individuals. The best outcome ever reported is normal intelligence, which has only been seen in individuals who do have some functioning enzyme activity and have had early and aggressive treatment in the first two years of life.

About 85% of individuals affected in the neonatal period (first hours to days of life) have a severe form, and 15% have a mild form. Of the individuals who begin to have signs and symptoms in infancy (the infantile form), about 50% have a severe form and 50% have a mild form. Overall, about 20% of all infants with the neonatal or infant form have a mild outcome. Occasionally, affected individuals have an intermediate outcome between mild and severe.

Individuals with a mild form of the disease can have variable degrees of developmental progress; they may learn to walk, interact with others and attend special education classes. One study found that up to 20% of surviving children learn to walk and say or sign words. These individuals may have little spasticity and they often develop a treatable seizure disorder.

Individuals with a severe form typically do not make developmental progress. At most, they may learn to sit and have very limited interaction with their environment. During the first year of life, they typically develop seizures that become increasingly difficult to treat, usually requiring multiple anticonvulsant medications. They typically have progressive spasticity early on, they have a tendency to develop scoliosis, and they often have swallowing dysfunction that requires tube feeding.[3]

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

In-Depth Information

The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.

Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine.

Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.

PubMed is a searchable database of medical literature and lists journal articles that discuss Glycine encephalopathy. Click on the link to view a sample search on this topic.

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My granddaughter has just been diagnosed with glycine encephalopathy. She is 3 months old. All the articles we have read are very complicated. What is glycine encephalopathy about? What treatment is there and what are her survival chances?
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Is it necessary to restrict protein intake in children that have this disorder? If so, what are the risks if protein intake is not restricted?
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My son has NKH and is my first born child. What is the chance my next child will have NKH if he has a different father?
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